sodium-perchlorate and Hypothyroidism

Topics: Carrier Proteins; Deafness; Goiter; Humans; Hypothyroidism; Membrane Transport Proteins; Mutation; Perchlorates; Sodium Compounds; Sulfate Transporters; Syndrome; Thyroid Hormones

Perchlorate competitively blocks iodide from entering the thyroid by an effect on the Na+/I- symporter thus preventing the further synthesis of thyroid hormone but has no effect on the iodination process itself. It is concentrated by thyroid tissue in a manner similar to iodide but is not significantly metabolized in the gland or peripherally. What is not settled is whether there are additional perchlorate effects on iodide transport. Perchlorate has a fast turnover in the body and requires frequent daily doses for therapy of thyrotoxicosis. Perchlorate appears to be substantially more effective against large iodide loads than the thionamides, and, with long-term iodide contamination, combined therapy of perchlorate (with < or = 1 g/day) and thionamides is recommended for the more severe cases of thyrotoxicosis that may result from excess iodide or iodide-generating organic compounds, as for example with amiodarone. After approximately 30 days, the perchlorate dosage can be tapered or stopped, continuing with thionamides alone. This markedly increases its safe use. Despite serious side effects during its early use, lower dosages and shorter treatment periods appear to have prevented such reactions in its recent reintroduction, mostly for amiodarone-induced thyroid dysfunction. Perchlorate can also protect against inhibition of thyroid function and the resulting hypothyroidism caused by excess iodide, presumably by reducing the formation of an iodinated inhibitor. The reduction of the iodide pool by perchlorate thus has dual effects--reduction of excess hormone synthesis and hyperthyroidism, on the one hand, and reduction of thyroid inhibitor synthesis and hypothyroidism on the other. Perchlorate remains very useful also as a single dose application in tests measuring the discharge of radioiodide accumulated in the thyroid as a result of many different disruptions in the further metabolism of iodide in the thyroid gland.

Topics: Amiodarone; Animals; Enzyme Inhibitors; Humans; Hypothyroidism; Iodide Peroxidase; Iodides; Kinetics; Perchlorates; Sodium Compounds; Thyroid Gland; Thyrotoxicosis

Investigate the effect of GC-1 on tolerance to exercise in rats with experimental hypothyroidism.. Hypothyroidism was induced with methimazole sodium and perchlorate treatment. Six groups with eight animals were studied: control group (C), hypothyroid group without treatment (HYPO); hypothyroidism treated with physiological doses of tetraiodothyronine (T4) or 10 times higher (10×T4); hypothyroidism treated with equal molar doses of GC-1 (GC-1) or 10 times higher (10×GC-1). After eight weeks, each animal underwent an exercise tolerance test by measuring the time (seconds), in which the rats were swimming with a load attached to their tails without being submerging for more than 10 sec. After the test, the animals were killed, and blood samples were collected for biochemical analysis, and the heart and soleus muscle were removed for weighing and morphometric analysis of the cardiomyocyte.. Hypothyroidism significantly reduced tolerance to exercise and, treatment with GC-1 1× or T4 in physiological doses recover tolerance test to normal parameters. However, high doses of T4 also decreased tolerance to physical exercise. Conversely, ten times higher doses of GC-1 did not impair tolerance to exercise. Interestingly, hypothyroidism, treated or not with T4 in a physiological range, GC-1 or even high doses of GC-1 (10X) did not change cardiomyocyte diameters and relative weight of the soleus muscle. In contrast, higher doses of T4 significantly increased cardiomyocyte diameter and induced atrophy of the soleus muscle.. Unlike T4, GC-1 in high doses did not modify tolerance to physical exercise in the rats with hypothyroidism.

Topics: Acetates; Animals; Exercise Tolerance; Hypothyroidism; Methimazole; Muscle, Skeletal; Myocytes, Cardiac; Perchlorates; Phenols; Rats, Wistar; Sodium Compounds; Swimming; Thyroid Hormone Receptors beta; Thyrotropin; Thyroxine; Triiodothyronine

Transient hypothyroidism induced by propyl-2-thiouracyl blocks postpartum Leydig cell development. In the present study, the effects of chronic hypothyroidism on the formation of this adult-type Leydig cell population were investigated, using a more physiological approach. Before mating, dams were put on a diet consisting of an iodide-poor feed supplemented with a low dose of perchlorate and, with their offspring, were kept on this diet until death. In the pups at day 12 postpartum, plasma thyroid-stimulating hormone levels were increased by 20-fold, whereas thyroxine and free tri-iodothyronine levels were severely depressed, confirming a hypothyroid condition. Adult-type progenitor Leydig cell formation and proliferation were reduced by 40-60% on days 16 and 28 postpartum. This was followed by increased Leydig cell proliferation at later ages, suggesting a possible slower developmental onset of the adult-type Leydig cell population under hypothyroid conditions. Testosterone levels were increased 2- to 10-fold in the hypothyroid animals between days 21 and 42 postpartum compared with the age-matched controls. Combined with the decreased presence of 5alpha-reductase, this implicates a lower production capacity of 5alpha-reduced androgens. In 84-day-old rats, after correction for body weight-to-testis weight ratio, plasma insulin-like factor-3 levels were 35% lower in the hypothyroid animals, suggestive of a reduced Leydig cell population. This is confirmed by a 37% reduction in the Sertoli cell-to-Leydig cell ratio in hypothyroid rats. In conclusion, we show that dietary-induced hypothyroidism delays but, unlike propyl-2-thiouracyl, does not block the development of the adult-type Leydig cell population.

Topics: Animals; Cell Differentiation; Cells, Cultured; Diet; Female; Fetal Nutrition Disorders; Hypothyroidism; Iodine; Leydig Cells; Male; Organ Size; Perchlorates; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Sodium Compounds; Testis; Time Factors

A lack of thyroid hormone, i.e. hypothyroidism, during early development results in multiple morphological and functional alterations in the developing brain. In the present study, behavioural effects of perinatal and chronic hypothyroidism were assessed during development in both male and female offspring of hypothyroid rats. To induce hypothyroidism, dams and offspring were fed an iodide-poor diet and drinking water with 0.75% sodium perchlorate; dams starting 2 weeks prior to mating and pups either until the day of killing (chronic hypothyroidism) or only until weaning (perinatal hypothyroidism) to test for reversibility of the effects observed. Neuromotor competence, locomotor activity and cognitive function were monitored in the offspring until postnatal day 71 and were compared with age-matched control rats. Early neuromotor competence, as assessed in the grip test and balance beam test, was impaired by both chronic and perinatal hypothyroidism. The open field test, assessing locomotor activity, revealed hyperactive locomotor behavioural patterns in chronic hypothyroid animals only. The Morris water maze test, used to assess cognitive performance, showed that chronic hypothyroidism affected spatial memory in a negative manner. In contrast, perinatal hypothyroidism was found to impair spatial memory in female rats only. In general, the effects of chronic hypothyroidism on development were more pronounced than the effects of perinatal hypothyroidism, suggesting the early effects of hypothyroidism on functional alterations of the developing brain to be partly reversible and to depend on developmental timing of the deficiency.

Topics: Age Factors; Animals; Behavior, Animal; Body Weight; Brain; Chronic Disease; Cognition; Disease Models, Animal; Female; Hypothyroidism; Iodine; Male; Memory; Motor Activity; Perchlorates; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Sodium Compounds; Thyroid Hormones; Thyrotropin

The low density lipoprotein (LDL) receptor-associated protein (RAP) is an endoplasmic reticulum (ER)-resident molecular chaperone for several LDL receptor family members and it also binds to thyroglobulin (Tg), the thyroid hormone precursor. Disruption of the RAP gene in thyrocytes results in impaired Tg secretion. To gain further insights into the function of RAP in the thyroid, we investigated whether its expression in thyrocytes is regulated by thyroid-stimulating hormone (TSH), a feature common to all proteins involved in thyroid hormone secretion. We found by immunofluorescence that in FRTL-5 cells cultured in the presence of TSH, RAP is expressed intracellularly. The levels of expression increased after exposure to TSH, beginning at 48 hours, in a concentration-dependent manner as observed by immunofluorescence and Western blotting. Expression of RAP was also increased by TSH in primary cultures of human thyrocytes as observed by Western blotting. In hypothyroid mice with high serum TSH, RAP was markedly increased compared with euthyroid mice as observed by immunohistochemistry and Western blotting. Based on these findings, we concluded that RAP is expressed by thyrocytes in a TSH-dependent manner, both in cultured thyroid cells and in vivo.

Topics: Animals; Antithyroid Agents; Blotting, Western; Chlorocebus aethiops; COS Cells; Epithelial Cells; Fluorescent Antibody Technique; Humans; Hypothyroidism; LDL-Receptor Related Protein-Associated Protein; Methimazole; Mice; Perchlorates; Rats; Sodium Compounds; Thyroid Gland; Thyrotropin; Up-Regulation

Topics: Child; Child, Preschool; Chile; Humans; Hypothyroidism; Infant; Infant, Newborn; Perchlorates; Risk Assessment; Sodium Compounds; Thyroid Function Tests; Water Pollutants, Chemical

The objectives of this study were to evaluate whether there were higher rates of primary congenital hypothyroidism (PCH) or elevated concentrations of thyroid-stimulating hormone (TSH) in a community where perchlorate was detected in groundwater wells. The adjusted PCH prevalence ratio and 95% confidence interval (CI) comparing the study community to San Bernardino and Riverside counties combined was 0.45 (95% CI=0.06-1.64). The odds ratios for elevated TSH concentration were 1.24 (95% CI=0.89-1.68) among all newborns screened and 0.69 (95% CI=0.27-1.45) for newborns whose age at screening was 18 hours or greater. Age of the newborn at time of screening was the most important predictor of the TSH level. These findings suggest that residence in a community with potential perchlorate exposure has not impacted PCH rates or newborn thyroid function.

Topics: California; Congenital Hypothyroidism; Female; Humans; Hypothyroidism; Infant, Newborn; Logistic Models; Male; Neonatal Screening; Perchlorates; Sodium Compounds; Thyrotropin; Water Pollutants, Chemical; Water Pollution, Chemical; Water Supply

Perchlorate is known to suppress thyroid function by inhibiting uptake of iodide by the human thyroid at doses of 200 mg/day or greater. A study was conducted to investigate the potential effects of perchlorate in drinking water on thyroid function in newborns and school-age children. A total of 162 school-age children and 9784 newborns were studied in three proximate cities in northern Chile that have different concentrations of perchlorate in drinking water: Taltal (100 to 120 micrograms/L), Chañaral (5 to 7 micrograms/L), and Antofagasta (non-detectable: < 4 micrograms/L). Among schoolchildren, no difference was found in thyroid-stimulating hormone levels or goiter prevalence among lifelong residents of Taltal or Chañaral compared with those of Antofagasta, after adjusting for age, sex, and urinary iodine. No presumptive cases of congenital hypothyroidism were detected in Taltal or Chañaral; seven cases were detected in Antofagasta. Neonatal thyroid-stimulating hormone levels were significantly lower in Taltal compared with Antofagasta; this is opposite to the known pharmacological effect of perchlorate, and the magnitude of difference did not seem to be clinically significant. These findings do not support the hypothesis that perchlorate in drinking water at concentrations as high as 100 to 120 micrograms/L suppresses thyroid function in newborns or school-age children.

Topics: Age Distribution; Child; Child, Preschool; Chile; Confidence Intervals; Data Collection; Drinking; Environmental Monitoring; Epidemiological Monitoring; Feasibility Studies; Female; Humans; Hypothyroidism; Incidence; Infant; Infant, Newborn; Linear Models; Logistic Models; Male; Odds Ratio; Perchlorates; Risk Factors; Sex Distribution; Sodium Compounds; Thyroid Function Tests; Water Pollution

IGF-I, IGF-I receptor and IGF-binding proteins (IGFBPs) are expressed in thyroid tissue and are associated with the function and growth of the thyroid. This study investigated the in vivo and in vitro effects of increased IGFBP-1 levels on the function and growth of the thyroid gland.. Transgenic mice which constitutively overexpress IGFBP-1 were used. These mice have a phenotype consistent with partial inhibition of IGF-I action.. Thyroid growth, morphology and hormonogenesis were determined in transgenic mice treated with goitrogens, sodium perchlorate and methimazole. In vitro cell proliferation in thyroid follicles was assessed in response to IGF-I and TSH.. Thyroid weight was increased in transgenic mice, relative to their body mass, whereas serum tri-iodothyronine (T(3)), thyroxine and T(3)-binding capacity were reduced, compared with wild-type. While an inverse relationship between T(3) and TSH was observed in both groups of goitrogen-treated mice, the slope of the line of best fit was less steep in transgenic mice compared with wild-type mice. Thyroid growth was less marked in transgenic than wild-type mice in response to goitrogens, although TSH levels were higher in goitrogen-treated transgenics. In vitro proliferative response of isolated thyroid follicles to IGF-I, but not to TSH, was reduced in transgenic, compared with wild-type mice.. The results of this study suggest that, while overexpression of IGFBP-1 attenuates IGF-I action in vitro, it enhances thyroid growth in vivo, presumably as a result of perturbations in thyroid function at multiple levels.

Topics: Aging; Animals; Antithyroid Agents; Cell Division; Disease Models, Animal; Hypothyroidism; In Vitro Techniques; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor I; Male; Methimazole; Mice; Mice, Transgenic; Organ Size; Perchlorates; Sodium Compounds; Thyroid Gland; Thyroid Hormones; Up-Regulation

Thirty eight children suffering from congenital primary permanent hypothyroidism were studied to determine the diagnostic impact of 123I scintigraphy in comparison to laboratory findings and ultrasonography.. In all patients 123I scintigraphy was performed after intravenous administration of 3.7 MBq 123I. If accumulation of the radiotracer in thyroid tissue occurred a perchlorate discharge test was performed subsequently.. Scintigraphy revealed athyrosis in 7 children. In 9 children a lingual thyroid was observed. Deficiency in iodine organification was diagnosed by a significant discharge of 123I in 15 patients. In four of these children the diagnosis of Pendred's syndrome could be established. Ectopic thyroid tissue could be demonstrated only by scintigraphy where clinical examination and sonography failed in the diagnosis in all cases. Hypoplasia of the thyroid gland as it was diagnosed in 2 cases by ultrasonography appeared to be unlikely because a normal 123I uptake was seen in these patients. In 2 patients with scintigraphic proven athyrosis an orthotopic gland had been falsely considered by ultrasound. In 44% of our patients the final diagnosis could only be established if 123I scintigraphy and perchlorate discharge test were performed.. This findings suggest that scintigraphy is indispensible in the correct diagnostic work up of congenital hypothyroidism.

Topics: Child; Child, Preschool; Congenital Hypothyroidism; Diagnosis, Differential; Female; Goiter; Hearing Loss, Sensorineural; Humans; Hypothyroidism; Iodine Radioisotopes; Male; Perchlorates; Radionuclide Imaging; Sodium Compounds; Syndrome; Thyroid Gland; Ultrasonography

The function and the growth of adult thyroid gland is controlled by the opposite actions of thyrotropin (TSH) and iodide, the main substrate of the gland. Iodide deprivation leads to stimulation of the thyroid, improving the efficiency of iodide transport for hormone biosynthesis. We have investigated cell proliferation and thyroid specific gene expression 24 and 48 h after administering KI to dogs previously treated with goitrogens and perchlorate. In the hypothyroid dogs T3 and T4 serum levels decreased from 53 +/- 4 to < 30 ng/dl and from 1.6 +/- 0.6 to < 1 microg/dl respectively; TSH concentration increased from 0.16 +/- 0.02 to 2.7 +/- 0.4 ng/ml. After a 24 h moderate KI treatment (300 microg KI/dog of +/- 10 kg) serum T3 concentrations rose higher than the initial normal values, while T4 concentrations increased to reach values equivalent to the normal level. The high TSH concentration did not change significantly. The hyperplasia of the chronically stimulated thyroid resulting from goitrogens/NaClO4 treatment was not modified by this short term treatment with KI. In contrast, KI decreased the weight of the total gland and the level of cell proliferation, as determined by the fraction of cells incorporating BrdU. The effect of acute administration of KI on the expression of four major thyroid genes, the TSH receptor (TSHr), thyroglobulin (Tg), thyroperoxidase (TPO), and Na+/I- symporter (NIS) was analyzed by Northern blot. Tg, TPO and NIS mRNA expressions were up-regulated by chronic stimulation. The expression of the mRNAs of TSHr and Tg did not significantly differ between hyperstimulated and KI-treated dogs while TPO and NIS mRNA expression decreased after a 48 h KI treatment. TPO and NIS are therefore the only of these four genes whose expression is acutely modulated by iodide in vivo. Under TSH stimulation low doses of iodide resulted in: (1) decreased cell proliferation, (2) reestablished synthesis and secretion of thyroid hormones, (3) diminished TPO and NIS mRNA expression. Notably low doses of iodide under the same conditions had no effect on Tg and TSHr mRNA expression.

Topics: Animals; Blotting, Northern; Carrier Proteins; Cell Division; Dogs; Gene Expression; Hypothyroidism; Iodide Peroxidase; Membrane Proteins; Perchlorates; Potassium Iodide; Propylthiouracil; Receptors, Thyrotropin; RNA, Messenger; Sodium Compounds; Symporters; Thyroglobulin; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Topics: Animals; Ascorbic Acid; Glutamates; Glutamic Acid; Hyperthyroidism; Hypothyroidism; Kinetics; Mitochondria, Heart; NAD(P)H Dehydrogenase (Quinone); Oxygen Consumption; Perchlorates; Phospholipids; Rats; Reference Values; Sodium Compounds; Succinates; Triiodothyronine

In soleus muscle fibres of hypothyroid rats, the membrane potential (Vm) and the intracellular K+ activity (aKi) were significantly lower than in control muscles. These results are consistent with the well-documented decrease in the number of Na(+)-K+ pumps which occurs in hypothyroid muscles. aNai was unchanged in the hypothyroid muscles but this may reflect a change in passive Na+ fluxes which has been reported to occur in association with changes in the number of pump units.

Topics: Animals; Body Weight; Hypothyroidism; Intracellular Membranes; Male; Muscles; Myocardium; Organ Size; Osmolar Concentration; Perchlorates; Potassium; Rats; Rats, Inbred Strains; Sodium; Sodium Compounds

Two cats with congenital hypothyroidism are described. In vivo discharge of accumulated labelled iodide by perchlorate administration revealed defective organification of iodide, which was complete in one cat and partial in the other. In the cat with the partial organification defect, thyroid tissue was obtained for biochemical studies. No membrane-bound peroxidase activity could be demonstrated. The activity was found in the 100,000 x g supernatant. It is suggested that the loose enzyme anchoring caused decreased availability of peroxidase and as a consequence reduced capacity for organic binding of trapped iodide.

Topics: Animals; Cat Diseases; Cats; Congenital Hypothyroidism; Hypothyroidism; Injections, Intravenous; Iodide Peroxidase; Iodine Radioisotopes; Male; Perchlorates; Sodium Compounds; Thyroid Gland

Amiodarone, an iodine-rich drug, represents at the present, at least in Europe, one of the most common sources of iodine-induced thyroid dysfunction. The drug may induce both hypothyroidism and thyrotoxicosis. In spite of the large iodine intake occurring during amiodarone therapy, 131I thyroid uptake is detectable in patients with amiodarone-iodine-induced hypothyroidism, irrespective of the presence or absence of underlying thyroid disease. In contrast, in patients with amiodarone-iodine-induced thyrotoxicosis, 131I thyroid uptake is normal or even elevated in those with co-existent underlying thyroid disorders, whereas it is very low in those with an apparently normal thyroid gland. Perchlorate discharge test was performed in 8 patients with hypothyroidism and in 5 patients with hyperthyroidism induced by amiodarone: a positive test was found in all hypothyroid patients and a negative test in all hyperthyroid patients.

Topics: Adult; Aged; Amiodarone; Female; Humans; Hyperthyroidism; Hypothyroidism; Iodine Radioisotopes; Male; Middle Aged; Perchlorates; Sodium Compounds; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones

The noradrenaline-induced energy dissipation rate was measured with a direct microcalorimeter in brown adipose tissue taken from rats acclimated to 34 degrees C (HA), perchlorate treated (PC) and heat acclimated-perchlorate treated (HAPC). The response to 10(-7) M NA was reduced by 45%, 47% and 86% in HA, PC and HAPC groups, respectively, as compared to a control group kept at 24 degrees C. In the same groups, the response to 10(-6) M NA was reduced by 34%, 7% and 64%, respectively. The specific activity of the soluble alpha-glycerophosphate dehydrogenase in brown fat from HA rats was reduced by 50%, whereas it was not altered in the PC animals. It is concluded that the sensitivity to noradrenaline of the brown adipose tissue thermogenic mechanisms is decreased in hypothyroidism, and that the acclimation temperature and the thyroid status per se each have a different influence on brown adipose tissue function.

Topics: Acclimatization; Adipose Tissue, Brown; Animals; Body Temperature Regulation; Glycerolphosphate Dehydrogenase; Hot Temperature; Hypothyroidism; Male; Norepinephrine; Perchlorates; Rats; Rats, Inbred Strains; Sodium Compounds

Amiodarone is a widely used antiarrhythmic drug, which contains 75 mg of iodide per 200 mg of active substance. Eight of our patients receiving long-term amiodarone therapy became hypothyroid. Seven of these patients had no previous history of thyroid dysfunction or goiter. Antithyroid antibodies were absent, and standard perchlorate discharge tests were positive in seven patients when hypothyroidism was diagnosed. In one patient, amiodarone therapy was withdrawn; over the next nine months, the hypothyroidism resolved, and results of the perchlorate discharge test reverted to normal. We conclude that amiodarone-induced hypothyroidism is similar to previously described iodide-induced hypothyroidism. It may develop in the absence of a previous history of thyroid disease, and all patients receiving long-term amiodarone therapy should therefore be regularly monitored for hypothyroidism.

Topics: Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Female; Humans; Hypothyroidism; Iodides; Iodine Radioisotopes; Male; Middle Aged; Perchlorates; Sodium Compounds; Thyroid Function Tests; Thyroid Gland; Thyroxine

In 172 patients over the age of 55, determinations were made of thyrotropin concentrations in plasma. Although they showed such symptoms or signs of hypothyroidism as puffy face, dry skin, general malaise, cold intolerance, or constipation, there were no clinical indications of overt hypothyroidism. All the patients were apparently in a normal nutritional state, without any specific medication that might cause thyroid abnormalities. Seventeen (six men and 11 women, 9.9 percent) of the 172 patients, aged 58 to 83, had elevated plasma thyrotropin levels, ranging from 12.1 microU/ml to 170 microU/nl. To investigate the characteristics of hypothyroidism in the elderly, the perchlorate discharge test was performed in these patients. In 15 of the 17 patients, 123I thyroid uptake diminished markedly immediately after the administration of 1 g perchlorate. Thirteen of these 15 patients showed markedly diminished thyroxine (T4) levels in serum, whereas the magnitude of diminution in serum 3,5,3'-triiodothyronine (T3) values was small. Two patients with the negative discharge results showed normal T4 and T3 levels in serum. Four patients had a very small goiter, and the remaining 13 patients had no detectable goiter. Fifteen of the 17 patients had no detectable circulating thyroid antibodies in repeated determinations, and the histologic features of Hashimoto's thyroiditis were not found in the thyroid specimens obtained from two patients. These findings suggest the existence of hypothyroidism attributable to iodine organification defect without evidence of autoimmune thyroiditis in some cases in elderly patients.

Topics: Aged; Antibodies; Biopsy; Female; Humans; Hypothyroidism; Male; Middle Aged; Perchlorates; Resins, Plant; Sodium Compounds; Thyroid Function Tests; Thyroid Gland; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Topics: Aged; Aging; Autoantibodies; Female; Humans; Hypothyroidism; Male; Middle Aged; Perchlorates; Sodium Compounds; Thyroid Gland; Thyroid Hormones